Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming.
Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming.
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小胶质细胞MT1激活通过调节代谢重编程抑制内毒素诱导的神经炎症。
DOI：
10.1111/acel.13375
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发表时间：
2021-06
期刊：
影响因子：
7.8
通讯作者：
Liu CF
中科院分区：
文献类型：
--
作者：
Gu C;Wang F;Zhang YT;Wei SZ;Liu JY;Sun HY;Wang GH;Liu CF
帕金森病(PD)是最常见的神经退行性疾病之一。虽然其发病机制尚不清楚，但大量研究表明，小胶质细胞介导的神经炎症在帕金森病的发病机制中起着重要作用。褪黑素受体1(MT1)广泛表达于黑质的神经胶质细胞和神经元。神经元MT1是一种神经保护因子，但小胶质细胞MT1功能障碍是否参与帕金森病的发病机制尚不清楚。在此，我们发现在1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)诱导的帕金森病小鼠模型中，黑质小胶质细胞中MT1的表达减少。小胶质细胞MT1的激活显著抑制脂多糖(LPS)诱导的神经炎症，而小胶质细胞MT1的缺失则加剧了这种炎症。小胶质细胞的代谢重编程被发现有助于MT1激活的抗炎作用。小胶质细胞MT1的激活可逆转脂多糖诱导的过度有氧糖酵解和氧化磷酸化受损(OXPHOS)。MT1正向调节丙酮酸脱氢酶α1(PDHA1)的表达，以增强OXPHOS并抑制有氧糖酵解。此外，在脂多糖处理的小胶质细胞中，MT1的激活降低了条件培养液对多巴胺能(DA)细胞系MES23.5的毒性。最重要的是，在内毒素刺激的小鼠模型中观察到了MT1激活的抗炎作用。综上所述，我们的研究表明MT1的激活通过调节其代谢重编程来抑制内毒素诱导的小胶质细胞的激活，这为小胶质细胞MT1的抗炎作用提供了一个机制。示意图显示代谢重编程参与MT1激活介导的抑制脂多糖诱导的小胶质细胞激活。小胶质细胞一旦受到内毒素的损伤，就会进入过度激活状态，同时将其代谢状态从OXPHOS转变为有氧糖酵解。然而，小胶质细胞MT1的激活可促进PDHA1的表达，导致逆转内毒素介导的小胶质细胞代谢重编程，从而抑制小胶质细胞的激活。
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Although its pathogenesis remains unclear, a number of studies indicate that microglia‐mediated neuroinflammation makes a great contribution to the pathogenesis of PD. Melatonin receptor 1 (MT1) is widely expressed in glia cells and neurons in substantia nigra (SN). Neuronal MT1 is a neuroprotective factor, but it remains largely unknown whether dysfunction of microglial MT1 is involved in the PD pathogenesis. Here, we found that MT1 was reduced in microglia of SN in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model. Microglial MT1 activation dramatically inhibited lipopolysaccharide (LPS)‐induced neuroinflammation, whereas loss of microglial MT1 aggravated it. Metabolic reprogramming of microglia was found to contribute to the anti‐inflammatory effects of MT1 activation. LPS‐induced excessive aerobic glycolysis and impaired oxidative phosphorylation (OXPHOS) could be reversed by microglial MT1 activation. MT1 positively regulated pyruvate dehydrogenase alpha 1 (PDHA1) expression to enhance OXPHOS and suppress aerobic glycolysis. Furthermore, in LPS‐treated microglia, MT1 activation decreased the toxicity of conditioned media to the dopaminergic (DA) cell line MES23.5. Most importantly, the anti‐inflammatory effects of MT1 activation were observed in LPS‐stimulated mouse model. In general, our study demonstrates that MT1 activation inhibits LPS‐induced microglial activation through regulating its metabolic reprogramming, which provides a mechanistic insight for microglial MT1 in anti‐inflammation. A schematic diagram shows the involvement of metabolic reprogramming in MT1 activation‐mediated inhibition of LPS‐induced microglial activation. Once microglia suffered LPS insults, microglia would transfer into over‐activated state, accompanied by converting their metabolic status from OXPHOS to aerobic glycolysis. However, microglial MT1 activation could promote PDHA1 expression, leading to reverse LPS‐mediated microglial metabolic reprogramming, thereby, suppressing microglial activation.
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影响因子：
44.1
作者：
通讯作者：
--
影响因子：
7.3
作者：
Cecon, Erika;Oishi, Atsuro;Jockers, Ralf
通讯作者：
Jockers, Ralf
影响因子：
3.5
作者：
Binukumar, B. K.;Bal, Amanjit;Gill, Kiran Dip
通讯作者：
Gill, Kiran Dip
DOI：
10.1146/annurev-pharmtox-010814-124742
发表时间：
2016
影响因子：
12.5
作者：
Liu J;Clough SJ;Hutchinson AJ;Adamah-Biassi EB;Popovska-Gorevski M;Dubocovich ML
通讯作者：
Dubocovich ML
影响因子：
7.8
作者：
Hefendehl JK;Neher JJ;Sühs RB;Kohsaka S;Skodras A;Jucker M
通讯作者：
Jucker M